Project Summary/abstract As many as 80% of the adult population experience back pain at some point in their lifetimes. Previous studies have indicated a link between back pain and intervertebral disc (IVD) degeneration in 40% of patients. Despite decades of research, robust therapies targeting underlying causes rather than symptoms are still in the earliest stages of development. Thus, there is an urgent need for alternative treatment, such as stem cell therapy, focused on correcting the underlying pathogenesis of DDD. Dr. Sheyn?s goal is to develop his academic career in musculoskeletal tissue engineering and stem cell therapy field, focusing on spine therapeutics. He has received excellent training in stem cell manipulation and gene delivery, in vivo models, bone tissue engineering and molecular biology. He has established solid track record of publications in the field and demonstrated strong capacity to conduct innovative research. The proposed training program is designed to build on Dr. Sheyn?s background and strengthen his expertise in specific areas most relevant to IVD therapeutics. Under the leadership and sponsorship of Dr. Clive Svendsen, the director of the Cedars-Sinai Regenerative Medicine Institute, Dr. Sheyn will gain experience in the three research areas: 1) development of soft tissue and cartilage biology; 2) immunology and inflammation; 3) quantitative imaging of soft tissue using magnetic resonance imaging (MRI). We will utilize formal workshops and courses and hands-on research supervised by seasoned mentors with extensive track record in these areas and mentorship to achieve those training goals. In the proposed study we will study the link between the possible mechanism of disc degeneration and the potential cell therapy. Firstly, we will investigate the developmental phenotype of novel induced pluripotent stem cell- derived notochordal cells as a potential source of cells to reverse the degeneration process and fibrosis of the disc. This aim will be conducted under mentorship of Dr. Lyons, well-established developmental and musculoskeletal biologist from UCLA and Dr. Hoyland, world expert in the notochord and IVD biology from Manchester U, UK. Secondly we will use the annular injury model of disc degeneration in pigs to study the role of pro-inflammatory and catabolic cytokines expressed by the NP cells under mentorship of Dr. Arditi, world known expert in immunology, inflammation and fibrosis., In Aim 3, the IVD degeneration will be assessed using MRI as shown in preliminary results, but also we will monitor the regeneration of the IVD using iPS-derived notochordal-like cells will be monitored under supervision of Dr. Li, world leader in MR research and imaging. Overall this study will improve our understanding of the disc degeneration and possible regeneration strategies, as well as will serve as excellent vehicle for Dr. Sheyn to strengthen his expertise in areas critical for addressing the DDD therapy and will place him in strong position to establish independent research to compete for substantial funding (R01).